Carbamate esters of physiologically active ph enenthylamines

ABSTRACT

Carbamate esters of physiologically active phenethylamines (e.g., amphetamine and ephedrine) are disclosed. These carbamates have ester moieties which are easily hydrolyzed in body fluids to release the phenethylamines at selected sites within the body.

I United States Patent [191 [111 3, Verbiscar June 26, 1973 CARBAMATEESTERS 0F [58] Field of Search 260/340.2, 47] C PHYSIOLOGICALLY ACTIVEPH ENENTHYLAMINES References Cited [76] Inventor: Anthony J. Verbiscar,160 E. V UNITED STATES PATENTS Montecito Avenue, Sierra Madre, 3,634,4901/1972 Carr et al 260/471 C Cailf. 91024 Primary Examiner-Lorraine A.Weinberger [22] Flled: 1971 Assistant ExaminerL. Arnold Thaxton 211 App}122 140 Attorney-Mason, Kolehmainen, Rathbum & Wyss Related U.S.Application Data 57 ABSTRACT [63] Continuation-impart of Ser. No.636,650, May 8,

1967, Pat. No. which is a Carbamate esters of physiologically actiyephenethyla mmes (e.g., amphetamine and ephedrine) arediscontmuation-m-part of Ser. No. 338,289, Jan. 17, 1964abandonedclosed. These carbamates have ester moieties WhlCh are easilyhydrolyzed in body fluids to release the [52] U S C] 260/471 C 260/340 2260/999 phenethylamines at selected sites within the body.

[51] Int. CL; C07c 125/06 10 Claims, No Drawings CARBAMATE ESTERS OFPHYSIOLOGICALLY ACTIVE PH ENENTHYLAMINES CROSS REFERENCE TO RELATEDAPPLICATIONS This application is a continuation-in-part of my copendingapplication Ser. No. 636,650 filed May 8, 1967, now U.S. Pat. No.3,600,427 granted Aug. 17, 1971, which is a continuation-in-part of myapplication Ser. No. 338,289 filed Jan. 17, 1964, now abandoned.

This invention relates to phenethylcarbamate esters which are readilyhydrolyzed in body fluids to release phenethylamines which arephysiologically active.

BRIEF SUMMARY OF THE INVENTION The phenethylcarbamates which comprisethis invention are represented by the following general formula whereinQ and Q are selected from hydrogen, halogen,

hydroxyl, lower alkoxy and benzyloxy substituents or together can be acarbonyldioxy radical, X is hydrogen or hydroxyl, X is hydrogen or loweralkyl, R is hydrogen or lower alkyl, Z is lower alkoxycarbonyl, carboxylor hydrogen, Z is nitro, phenyl or hydrogen, and Y is hydrogen or loweralkyl, but 2 and Z are not both hydrogen. These compounds arederivatives of physiologically active phenethylamines. The estermoieties which are released as alcohols on biological hydrolysis havelow toxicity.

DETAILED DESCRIPTION OF THE INVENTION As explained more fully in mycopending application Ser. No. 636,650, now U.S. Pat. No. 3,600,427,Aug. 17, 1971, which is incorporated herein by reference, it is possibleto make physiologically active amines available at the proper site inmammals for biological activity by modifying such amines to producecarbamates which in vivo liberate the parent physiologically activeamine at the appropriate site in mammals. This is achieved by convertingphysiologically active amines into certain relatively easilyhydrolisable carbamates whereby it is possible to control the selectiveabsorption, penetration rate or release of the physiologically activeamines and achieve prolongation of drug action at preselected sites inmammals. These ends are accomplished by converting the physiologicallyactive amines into carbamates which can be selected to affect lipoidsolubility, as well as solubility in other body fluids. When thecarbamate reaches the preselected site, it is hydrolyzed physiologicallyto release the amine so that the latter may exert its physiologicalinfluence at that site.

The ester radical represented by the moiety in the general formula aboveis so selected as to assist biological hydrolysis anchimerically torelease the physiologically active phenylethylamine. The carbamatesexhibit biphasic effects in mice, including reduction in body tensionand central and mild autonomic activity. The phenylethylamines which arereleased are central nervous stimulants and sympathomimetic drugs. Thephysiological properties of this class, particularly amphetamine,ephedrine and dopamine, are well established In the general formulaabove, the lower alkoxyl radicals which Q and Q can represent as thosecontaining one to four carbon atoms, such as methoxyl and ethoxyl. Thelower alkyl radical that X and Y can represent and the alkoxyl group inthe alkoxylcarbon'yl substituent represented by Z also contain one tofour carbon atoms, preferably methyl and ethyl.

The invention is disclosed in more detail by means of the followingexamples which are provided for purposes of illustration only. It willbeunderstood by those skilled in the art that various modifications inreagents, operating conditions and the like may be made within the scopeof the invention as disclosed herein.

EXAMPLE 1 Carbamate from Ethyl Lactate and Amphetamine A mixture of 5.53g. of DL-amphetamine sulfate, 3.4 g. of sodium carbonate, 50 ml. ofchloroform and 20 ml. of water was cooled to 10C. A solution of 5.8 g.of ethyllactyl chloroformate [a-carbethoxyethyl chloroformate] in 20 ml.of chloroform was added with good stirring over 10 minutes, keeping thetemperature between lO-l 5C. After an hour the cooling bath was removedand the mixture was allowed to stir for 0.5 hours at room temperature,after which time carbon dioxide was no longer evolved. The organic layerwas separated and washed successively with 20 ml. of 5 percenthydrochloric acid, 20 ml. of water, and dried over sodium sulfate. Thesolvent was evaporated leaving an oil which was taken up in 30 ml. ofpetroleum ether, decolorized with charcoal, filtered and the filtratecooled in the refrigerator. The 6.8 g. of clear, colorless oil whichprecipitated gave a single spot on thin layer chromatography, showedinfrared absorption peaks at 5.67 microns and 5.76 microns, and gave acorrect elemental analysis for the ethyllactate carbamate of DL-amphetamine [a-carbethoxyethyl a-methyl-B-phenylethylcarbamate]. Theproduct has the formula over 15 minutes keeping the temperature below8C..

The solution was stirred in the ice-salt bath for 1 hour longer and thenat room temperature for 1.5 hours, after which time a solidprecipitated. A ml. portion of water was added, the organic layer wasseparated and washed successively with 100 ml. of 5 percent hydrochloricacid and 100 ml. of water. After drying over calcium chloride,distillation yielded 36 g. (66 percent of ethyllactyl chloroformate as aclear, colorless lachrymatory oil, b.p. 55-57C. at 4 mm. An infraredspectrum in carbon disulfide showed two strong sharp peaks at 5.58microns and 5.66 microns.

EXAMPLE 2 Carbamate from Ethyl Lactate and Ephedrine This compound[a-carbethoxyethyl N-methyl-amethyl-B-hydroxy-B-phenylethylcarbamate]was prepared by the procedure of Example 1, but with an equivalentquantity of L-ephedrine sulfate in lieu of the DL-amphetamine sulfate.It was a colorless oil which gave a single spot on thin layerchromatography. It has the formula EXAMPLE 3 2-Methyl-2-nitropropylD-a-methyl-B-phenylethylcarbamate A mixture of 10 grams (0.027 mole) ofD- amphetamine sulfate, 6.2 grams of sodium carbonate, 100 ml. ofchloroform and 50 ml. of water was cooled to 10C. A solution of 11 gramsof 2-methyl-2 nitropropyl chloroformate in 30 ml. of chloroform wasadded over minutes with cooling and then the mixture was stirred for anadditional 2 hours at room temperature. The two clear layers wereseparated, and the chloroform phase was washed with 50 ml. of 5 percenthydrochloric acid, water, then dried over sodium sulfate. The solventwas vacuum evaporated and the resulting oil was recrystallized frompetroleum ether (60-l10) giving 10.53 grams (70 percent) of whitecrystals, m.p. 5557C. It has the formula EXAMPLE 52-Methyl-2-nitropropyl barnate 4-chloro-B-phenylethylcar- A mixture ofgrams (0.0643 mole) of 2-(pchlorophenyl) ethylamine, 3.82 grams ofsodium carbonate, 40 m1. of water, 100 ml. of solvent A and 12.7

grams of 2-methyl-2-nitropropy1 chloroformate was re-. acted as inExample 3. The workup yielded 19 grams (98 percent) of an oil which washomogeneous on thin layer chromatography, using Merck silica gel G, 95:5benzene:methanol developer, iodine detection, with an 11 0.71.Recrystallization from isopropyl ether petroleum ether or from carbontetrachloride-petroleum ether gave the product as white needles, m.p.40.542.5C. it has the formula EXAMPLE 6 2-Methyl-2-nitropropyl3,4dihydroxy-B-phenyethylcarbamate A mixture of 1.9 grams (0.010 mole)of dopamine hydrochloride, 3.08 grams of 2methyl-2-nitropropylchloroformate, 1.17 grams of sodium carbonate, 10 ml. of water, 10 ml.of tetrahydrofuran and 60 ml. of ethyl acetate was stirred at 10C for 30minutes, and then at room temperature for another 90 minutes. Themixture was further diluted with 10 ml. of water and 40 ml. of ethylacetate, and the organic phase was washed with 3 percent hydrochloricacid, water, and then dried over sodium sulfate. Evaporation of thesolvent left an oil, most of which dissolved in 90 ml. of warm benzene.After decolorization with Nuchar Cl90-N on slow cooling, 1.35 grams ofwhite crystalline product, m.p. ll7l21C. was collected. A thin layerchromagram on Eastman 6060 sheets using a 9:1 benzene methanol developerwith iodine detection gave a spot at R/0.54 and indicated that theproduct was essentially homogeneous. It has the formula EXAMPLE 73,4-carbonyldioxy-'B- product.

The chloroform solution of the 2-methyl2- nitropropyl3,4-dihydroxy-B-phenylethylcarbamate was cooled in an ice-propanol bathand 1 .4 grams of triethylarnine were added, followed by a solution of 2grams of phosgene in 4 ml. of chloroform. The mixture was stirred in thebath for 20 minutes, then for another hour at room temperature. Afterwashing with water the solution was dried over sodium sulfate.Evaporation of the solvent left 2.0 grams of straw colored oil. AEXAMPLE l TLC on Eastman 6060 chromagram sheet using 9:]benzene-methanol developer showed the oil to be homogeneous with anR,0.82. The product is insoluble in petroleum ether, soluble in benzeneand toluene, and oils out of carbon tetrachloride. It has the formulaa-Carbomethoxybenzyl 4-chloro-B-phenylethylcarbamate Using 7 grams of4-chloro-B-phenylethylamine hydrochloride, 2.65 grams of sodiumcarbonate, 25 ml. of water and 50 ml. of l M a-carbomethoxybenzylchloroformate solution, this reaction was run as in Example 1 L 8.Recrystallization of the product from petroleum v OHECHENHGoouhi'cmether (60-l provided 13.8 grams of white crystals, 0...( N 10 01 mp.8l82C. It has the formula EX E 8 I (IIOOCIM A. a-Carbomethoxybenzylchloroformate 15 CHGHNHCOO01mm A solution of 53 grams of phosgene in 200ml. of 501- vent A was maintained at O-lOC. while 50 grams of methylmandelate in 500 ml. of solvent A was added over minutes with goodstirring. A solution of 30 grams of triethylamine in 100 ml. of solventA was 20 EXAMPLE 11 added next over 20 minutes as a white precipitateformed, and then the mixture was stirred for 3 /2 hours out of thecooling bath. After this time 200 ml. of water was added cautiously. Theorganic phase was separated, washed with brine and dried over calciumchloride. Excess solvent was evaporated under vacuum and dry benzene wasadded to the residual oil to bring the concentration ofa-carbomethoxylbenzyl chloroformate to 1 molar. This solution was usedin subsequent carbamate ester preparations.

B. a-Carbomethoxybenzyl B-phenylethylcarbamate A solution of 7.9 gramsof B-phenylethylamine hydrochloride, 5.82 grams of sodium carbonate and60 ml. of water was cooled to 10. There was then added with goodstirring over 10 minutes 60 ml. of l M a-carbomethoxybenzylchloroformate solution and stirring @009, was continued for 2 /2 hours.Chloroform was added and the organic phase was separated, washed with100 ml. of 5 percent hydrochloric acid, 50 ml. of water, then dried oversodium sulfate. Evaporation of the sol- 40 vent left an oil whichcrystallized on standing. Recrystallization from isopropyl ether gave 11 grams of a-cara-Carbomethoxybenzyl3,4-dibenzyloxy-B-phenylethylcarbamate A mixture of 10 grams of3,4-dibenzyloxy-B- phenylethylamine hydrochloride, 3.53 grams of sodiumcarbonate, 40 ml. of water, 40 ml. of chloroform and chloroformatesolution was reacted and worked up as in Example 8. Eventually there wasisolated 18.6 grams of the product as an oil. This was dissolved incarbon tetrachloride and precipitated by the addition of petroleumether. A thin layer chromatogram on Merck silica gel G using 95:5benzene-methanol developer showed this product to be essentiallyhomogeneous with an R,0.74. It has the formula bomethoxybenzyl,B-phenylethylcarbamate as white Hydrogenation in the presence of aplatinum catalyst crystals, m.p. 85.587.5C. The product washomogeremoves the benzyl radicals and produces a-carbeneous on thinlayer chromatography using Merck silica thoxybenzyl,B-(3,4-dihydroxyphenyl)ethylcarbamate. gel G and a 95:5benzenezmethanol developer. It has I claim: the formula 1. A compound ofthe formula (100011; omcnmncoooncm.

' Q. R z Z CHX-CIIXI IC0O-d)Ilrd3ll-Y Q1 EXAMPLE 9 a-CarboxybenzylB-phenylethylcarbamate A small quantity of a-carbomethoxybenzyl,B-phenylethyl carbamate was suspended in dilute sodium hywherem Q andQ, are Selected r hydrogen halogen droxide in which it slowly dissolvedwith hydrolysis. hydroxyl' and P f subsmuems or together can A idifi iprovided wearbowbenzfl B phenyle be carbonyldioxy radical, X 18 hydrogenor hydroxyl, thylaminecarbamate as white crystals, m.p. 8184-C., Xhydrogen or lower alkyl' R hydrogen or lower alkyl, Z is loweralkoxycarbonyl, carboxyl or hydrogen.

V Z is nitro, phenyl or hydrogen, and Y is hydrogen or (1mm lower alkyl,but Z and Z are not both hydrogen.

I (HM-"MNmnmlmvnllfi 6 2. A compound as defined by claim 1 wherein Z ishaving the formula lower alkoxycarbonyl and Z and Y are hydrogen.

3. A compound as defined by claim 2 wherein R is hydrogen.

7 8 4. A compound as defined by claim 3 wherein X is 8. A compound asdefined by claim 7 wherein Q and hydroxyl and X is methyl. Q arehydroxyl.

5. A compound as defined by claim 4 wherein Q and 9. A compound asdefined by claim 2 wherein Z is Q are hydrogen. carbalkoxyl or earboxyl,Z is phenyl and Y is hydro- 6. A compound as defined by claim 2 whereinZ is hy- 5 gen. drogen, Z is nitro and Y is lower alkyl. 10. A compoundas defined by claim 9 wherein Q and 7. A compound as defined in claim 6wherein X, X Q are benzyloxy. and R are hydrogen.

2. A compound as defined by claim 1 wherein Z is lower alkoxycarbonyland Z'' and Y are hydrogen.
 3. A compound as defined by claim 2 whereinR is hydrogen.
 4. A compound as defined by claim 3 wherein X is hydroxyland X'' is methyl.
 5. A compound as defined by claim 4 wherein Q and Q''are hydrogen.
 6. A compound as defined by claim 2 wherein Z is hydrogen,Z'' is nitro and Y is lower alkyl.
 7. A compound as defined in claim 6wherein X, X'' and R are hydrogen.
 8. A compound as defined by claim 7wherein Q and Q'' are hydroxyl.
 9. A compound as defined by claim 2wherein Z is carbalkoxyl or carboxyl, Z'' is phenyl and Y is hydrogen.10. A compound as defined by claim 9 wherein Q and Q'' are benzyloxy.